HIV causes a chronic infection characterized by depletion of CD4+ T lymphocytes and, at late stages, severe bone marrow abnormalities. Despite the development of drugs that inhibit viral spread, HIV has been difficult to treat because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy and the immune response. We have used CD34+ cells from infected people as well as in vitro studies of wild type HIV to demonstrate infection and killing of CD34+ hematopoietic progenitor cells (HPCs). Importantly, the HPCs that became infected included primitive, multi-potent cells. In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. This application proposes studies, which will determine whether HIV-1 envelope tropism targets progenitor cells with different developmental capacities and whether HIV-1 infects bona fide stem cells. PUBLIC HEALTH RELEVANCE: The overall goal of this research is to develop improved treatments for HIV-infected people by determining which cell types are responsible for persistent disease.